Plakophilin 3 (PKP3) is a desmosomal protein that belongs to the armadillo family of cell adhesion and signaling proteins. Our preliminary data demonstrate that loss of Pkp3 function in epidermal keratinocytes leads to an up regulation of several armadillo proteins (plakophilin 1, plakoglobin, -catenin), reduced cell migration and an increased susceptibility to oncogene-mediated transformation. Consequently, we concluded that PKP3 acts as a tumor suppressor gene in stratified epithelia. Our data provide a mechanistic explanation for the observed correlation between PKP3 downregulation and increased malignancy observed in human squamous cell carcinomas. We also found that PKP3 interacts with G3BP and Rack-1 proteins that are thought to regulate cellular stress response, such as cell death and cell survival decisions in cells exposed to heat or chemical stress. The successful completion of this project will lead to the identification of novel cell signaling pathways in keratinocytes that are important for the cellular stress response, cell migration and the susceptibility of keratinocytes to tumor development.